The objectives of the proposed research are to provide information concerning factors regulating the secretion of glucagon in man and their possible alterations in disorders of carbohydrate metabolism. The specific questions posed are: 1) Does dietary composition alter "basal" or "stimulated" phases of glucagon release? 2) Is glucagon secretion subject to regulation through the autonomic nervous system? 3) Is glucagon synthesized, stored and released from multiple compartments within the alpha cell? 4) Is alpha cell function altered in man with age? 5) Is regulation of glucagon secretion deranged in diabetes mellitus? The following specific approaches will be employed: 1) Evaluation of glucagon secretory mechanisms by acute and chronic alteration to the composition of carbohydrate, fat and protein of the diet. 2) The contribution of the autonomic nervous system in glucagon regulation will be assessed pharmacologically using IV catecholamines and their congeners without and with specific blockers of alpha and beta adrenergic receptors. Physiologically and pharmacologically induced stress will also be induced to test their effects on glucagon secretion with and without adrenergic blockade. In the baboon, the effects on glucagon release after intracarotid and intrahypothalamic instillations of varieties of substrates, e.g. glucose, will be evaluated. 3) The presence of Phase I and Phase II compartments for glucagon release will be sought by administering acute pulses of substrate known to release glucagon and measurement of possible biosynthetic precursors. 4) Measurement of glucagon responses in populations of various ages will be made using appropriate stimuli and inhibitors of alpha cell function. 5) Assessment of glucagon secretion in patients with diabetes mellitus will be attempted by comparing responses to various alpha cell stimuli between normal and diabetic populations.